Background: Early growth response genes (EGR1, 2, 3, and 4) encode a family of nuclear proteins that function as transcriptional regulators, and are involved in the regulation of synaptic plasticity, learning, and memory. Recent studies implicate that this gene family might be involved in the pathogenesis of schizophrenia. Methods: We conducted a genetic association analysis of 14 SNPs selected from the EGR1, 2, 3, and 4 genes in 564 patients with schizophrenia and 564 control subjects. We also conducted Western blot analysis and promoter activity assay to characterize the genetic association of the EGR gene family and schizophrenia. Results: We detected a significant over-representation of the C/C genotype of the rs9990(p=0.012) and the haplotype C-G-C of the EGR2 gene (p=0.015) in female schizophrenia. Further study showed that the mRNA levels of the EGR2 in the lymphoblastoid cell lines in female schizophrenia were significantly higher than that in female control subjects (p=0.002). In addition, we detected 4 SNPs (rs6747506, rs6718289, rs2229294, and rs3813226) of the EGR4 gene associated with male schizophrenia. Reporter gene assay of the haplotypes derived from two promoter SNPs (rs6747506 and rs6718289) showed that the haplotype T-A that was associated with male schizophrenia had significantly reduced promoter activity. No association of theEGR1 and 3 genes with schizophrenia was detected in this study. Discussion: Our data indicate that elevated expression of the EGR2 might be associated with the pathogenesis of schizophrenia in females, while reduced EGR4 expression might be associated with schizophrenia in males.
